Abstract::Alzheimer’s disease (AD) is a degenerative neurological disease characterized by a loss
of memory and cognitive ability. One of the main factors influencing the development of AD is
the accumulation of amyloid β (Aβ) plaque in the brain. The sequential production of Aβ is mediated
by two enzymes: gamma-secretase and β-secretase (BACE1). The goal of beta-secretase inhibitors
is to prevent the initial cleavage of amyloid precursor protein (APP), which reduces the
production of amyloid-β peptides by limiting the substrate available for gamma-secretase. Simultaneously,
gamma-secretase modulators are engineered to specifically modify enzyme performance,
reducing the synthesis of the harmful Aβ42 isoform while maintaining vital physiological processes.
Targeting both secretases reduces amyloidogenic processing synergistically. Selective inhibitors,
which have been recently developed, have also shown good clinical development. They can
reduce Aβ levels effectively with minimal side effects. The therapeutic strategy also underlines
the importance of early therapy intervention in the preclinical AD phase for an optimum effect. Although
there are some problems in the optimization of drug delivery and the alleviation of side effects,
targeting beta and gamma secretases remains a promising direction. However, all these
strategies still need more research and clinical testing to improve existing treatments and develop
new, efficient Alzheimer's disease therapies. This review seeks to examine the therapeutic
promise of β- and γ-secretase inhibition in Alzheimer's disease and review recent progress, challenges,
and new dual-inhibition approaches.